Cumulative Incidence of Thiazide-Induced Hyponatremia : A Population-Based Cohort Study.

BACKGROUND: According to drug labels, the frequency of thiazide-induced hyponatremia is unknown or uncommon to very rare (that is, <1 in 10 000 to <1 in 100), but the exact burden remains unclear. OBJECTIVE: To estimate the increase in the cumulative incidence of hyponatremia using thiazide diuretics compared with nonthiazide antihypertensive drugs in routine clinical practice. DESIGN: Population and register-based cohort study using target trial emulation. SETTING: Denmark, 1 January 2014 to 31 October 2018. PARTICIPANTS: Two target trials were emulated among persons aged 40 years or older who had no recent prescription for any antihypertensive drug, had no previous hyponatremia, and were eligible for the studied antihypertensive treatments. The first target trial emulation compared new use of bendroflumethiazide (BFZ) versus a calcium-channel blocker (CCB). The second target trial emulation compared new use of hydrochlorothiazide plus a renin-angiotensin system inhibitor (HCTZ-RASi; that is, combination pill) versus a RASi alone. MEASUREMENTS: Two-year cumulative incidences of sodium levels less than 130 mmol/L using stabilized inverse probability of treatment-weighted survival curves. RESULTS: The study compared 37 786 new users of BFZ with 44 963 of a CCB and 11 943 new users of HCTZ-RASi with 85 784 of a RASi. The 2-year cumulative incidences of hyponatremia were 3.83% for BFZ and 3.51% for HCTZ-RASi. The risk differences were 1.35% (95% CI, 1.04% to 1.66%) between BFZ and CCB and 1.38% (CI, 1.01% to 1.75%) between HCTZ-RASi and RASi; risk differences were higher with older age and higher comorbidity burden. The respective hazard ratios were 3.56 (CI, 2.76 to 4.60) and 4.25 (CI, 3.23 to 5.59) during the first 30 days since treatment initiation and 1.26 (CI, 1.09 to 1.46) and 1.29 (CI, 1.05 to 1.58) after 1 year. LIMITATION: The study assumed that filled prescriptions equaled drug use, and residual confounding is likely. CONCLUSION: Treatment initiation with thiazide diuretics suggests a more substantial excess risk for hyponatremia, particularly during the first months of treatment, than indicated by drug labeling. PRIMARY FUNDING SOURCE: Independent Research Fund Denmark.

Booster vaccination with SARS-CoV-2 mRNA vaccines and myocarditis in adolescents and young adults: a Nordic cohort study.

BACKGROUND AND AIMS: The SARS-CoV-2 mRNA vaccines are associated with an increased risk of myocarditis. This association appears to be strongest in male adolescents and younger males and after the second dose. The aim was to evaluate the risk of myocarditis following SARS-CoV-2 mRNA booster vaccination in 12-to-39-year-olds. METHODS: A multinational cohort study was conducted using nationwide register data in Denmark, Finland, Norway, and Sweden and comprising all 8.9 million individuals residing in each of the four countries. Participants were followed for an inpatient diagnosis of myocarditis. In each of the four countries, Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) of myocarditis comparing vaccination schedules, with associated 95% confidence intervals (CIs). Country-specific results were combined in meta-analyses. RESULTS: A total of 8.9 million residents were followed for 12 271 861 person-years and 1533 cases of myocarditis were identified. In 12-to-39-year-old males, the 28-day acute risk period following the third dose of BNT162b2 or mRNA-1273 was associated with an increased incidence rate of myocarditis compared to the post-acute risk period 28 days or more after the second dose [IRR 2.08 (95% CI 1.31-3.33) and 8.89 (2.26-35.03), respectively]. For females, the corresponding IRR was only estimable for BNT162b2, 3.99 (0.41-38.64). The corresponding absolute risks following the third dose of BNT162b2 and mRNA-1273 in males were 0.86 (95% CI 0.53-1.32) and 1.95 (0.53-4.99) myocarditis events within 28 days per 100 000 individuals vaccinated, respectively. In females, the corresponding absolute risks following the third dose of BNT162b2 were 0.15 (0.04-0.39) events per 100 000 individuals vaccinated. No deaths occurred within 30 days of vaccine-related cases. CONCLUSIONS: The results suggest that a booster dose is associated with increased myocarditis risk in adolescents and young adults. However, the absolute risk of myocarditis following booster vaccination is low.

SARS-CoV-2 Infection and Postacute Risk of Non-Coronavirus Disease 2019 Infectious Disease Hospitalizations: A Nationwide Cohort Study of Danish Adults Aged ≥50 Years.

BACKGROUND: Reports suggest that the potential long-lasting health consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may involve persistent dysregulation of some immune populations, but the potential clinical implications are unknown. We investigated the associated risk of hospitalization due to non-coronavirus disease 2019 (COVID-19) infectious diseases following the postacute phase of SARS-CoV-2 infection. METHODS: By cross-linking data from the comprehensive Danish test and surveillance system for COVID-19 together with nationwide healthcare and demographic registers, we established a study cohort of 2 430 694 individuals aged ≥50 years, from 1 January 2021 to 10 December 2022, with no evidence of SARS-CoV-2 infection prior to study entry. Using Poisson regression, we compared the outcome rates of non-COVID-19 infectious disease hospitalizations following the acute phase of (a first) SARS-CoV-2 infection (defined as ≥29 days since the day of infection) in recovered individuals with rates among SARS-CoV-2-uninfected individuals. RESULTS: Among 2 430 694 included individuals (mean age, 66.8 [standard deviation, 11.3] years), 930 071 acquired SARS-CoV-2 infection during follow-up totaling 4 519 913 person-years. The postacute phase of SARS-CoV-2 infection was associated with an incidence rate ratio (IRR) of 0.90 (95% confidence interval [CI]: .88-.92) for any infectious disease hospitalization. Findings (IRR [95% CI]) were similar for upper respiratory tract (1.08 [.97-1.20]), lower respiratory tract (0.90 [.87-.93]), influenza (1.04 [.94-1.15]), gastrointestinal (1.28 [.78-2.09]), skin (0.98 [.93-1.03]), urinary tract (1.01 [.96-1.08]), certain invasive bacterial (0.96 [.91-1.01]), and other (0.96 [.92-1.00]) infectious disease hospitalizations and in subgroups. CONCLUSIONS: Our study does not support an increased susceptibility to non-COVID-19 infectious disease hospitalization following SARS-CoV-2 infection.

Association of glucagon-like peptide-1 receptor agonists with serious liver events among patients with type 2 diabetes: A Scandinavian cohort study.

BACKGROUND AND AIMS: Clinical trials suggest that glucagon-like peptide-1 (GLP-1) receptor agonists may have beneficial effects on NAFLD, but the impact on hard hepatic end points is unknown. We assessed the association between the use of GLP-1 receptor agonists and the risk of serious liver events in routine clinical practice. APPROACH AND RESULTS: Cohort study using data from nationwide registers in Sweden, Denmark, and Norway, 2007-2020, including 91,479 initiators of GLP-1 receptor agonists and 244,004 initiators of the active comparator, dipeptidyl peptidase-4 inhibitors, without a history of chronic liver disease other than NAFLD/NASH. The primary outcome was serious liver events: a composite of incident compensated and decompensated cirrhosis and HCC. Secondary outcomes were the individual components of the primary outcome. Cox regression was used to estimate HRs, using propensity score weighting to control for confounding. Users of GLP-1 receptor agonists had 608 serious liver events (adjusted incidence rate: 16.9 events per 10,000 person-years), compared with 1770 events among users of dipeptidyl peptidase-4 inhibitors (19.2 events per 10,000 person-years). The adjusted HR was 0.85 (95% CI: 0.75 to 0.97), and the rate difference was -2.1 (-4.4 to 0.1) events per 10,000 person-years. In secondary outcome analyses, the adjusted HR was 0.85 (0.75 to 0.97) for compensated and decompensated cirrhosis and 1.05 (0.80 to 1.39) for HCC. CONCLUSIONS: The use of GLP-1 receptor agonists was associated with a significantly reduced risk of serious liver events, driven by a reduction of compensated and decompensated cirrhosis.

Association between atopic disease and vaccination granulomas: A nested case-control study.

BACKGROUND: Vaccination granulomas are observed in 1% of all children vaccinated with an aluminium-adsorbed vaccine. Most children with granulomas also have aluminium contact allergy (CA). CA and atopic diseases are both highly prevalent among children and may be associated. OBJECTIVE: To investigate the association between vaccination granulomas and atopic dermatitis (AD), asthma and rhinitis in children. METHODS: We sourced a cohort of all Danish children born from 2009 to 2017 and conducted a nested case-control study, with cases defined as children with vaccination granulomas, matched to controls 1:10 on sex, socioeconomic class, gestational age and season of birth. All cases and controls were vaccinated with aluminium-adsorbed vaccines and followed until their second birthday. We used conditional logistic regression to estimate the odds ratios (ORs). RESULTS: The study included 2171 cases with vaccination granulomas, and 21 710 controls. Children with a diagnosis of AD had a significantly higher risk of a vaccination granuloma (OR 1.50, 95% confidence intervals [CI] 1.25-1.80). No significant association was found between granulomas and asthma or rhinitis. The association between granulomas and AD was even higher in an additional sensitivity-analysis, following the children until their fourth birthday (OR 2.71, 95% CI 2.36-3.11). CONCLUSION: AD was significantly associated with vaccination granulomas, but not with other atopic diseases, within both the first 2 and 4 years of life.

Post-acute symptoms 4 months after SARS-CoV-2 infection during the Omicron period: a nationwide Danish questionnaire study.

Post-acute symptoms are not uncommon after SARS-CoV-2 infection with pre-Omicron variants. How Omicron and COVID-19 booster vaccination influence the risk of post-acute symptoms is less clear. We analyzed data from the nationwide Danish questionnaire study EFTER-COVID comprising 44,553 individuals ≥15 years old, tested between July 2021 and January 2022, in order to evaluate the association of the Omicron variant and COVID-19 booster vaccination with post-acute symptoms and new-onset general health problems, four months after infection with SARS-CoV-2. Risk differences (RDs) were estimated by comparing Omicron -cases to controls, Omicron to Delta -cases, and Omicron vaccinated cases with three to -two doses, adjusted for age, sex, BMI, self-reported chronic diseases, Charlson comorbidity index, healthcare occupation, and vaccination status. Four months after testing for SARS-CoV-2 during the Omicron period, cases experienced substantial post-acute symptoms and new-onset health problems compared to controls; the largest RD was observed for memory issues (RD=7.2%, 95%CI: 6.4 to 8.1). However, risks were generally lower than in the Delta period, particularly for dysosmia (RD=-15.0%, 95%CI: -17.0 to -13.2) and dysgeusia (RD=-11.2%, 95%CI: -13.2 to -9.5). Booster vaccination was associated with fewer post-acute symptoms and new-onset health problems, four months after Omicron infection, compared to two COVID-19 vaccine doses.

Use of DPP4 Inhibitors and GLP-1 Receptor Agonists and Risk of Intestinal Obstruction: Scandinavian Cohort Study.

BACKGROUND & AIMS: Concerns have been raised that the incretin-based diabetes drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists may increase the risk of intestinal obstruction. We aimed to assess the association between use of DPP4 inhibitors and GLP-1 receptor agonists and the risk of intestinal obstruction. METHODS: Using data from nationwide registers in Sweden, Denmark, and Norway, 2013-2021, we conducted 2 cohort studies, one for DPP4 inhibitors and one for GLP-1 receptor agonists, to investigate the risk of intestinal obstruction as compared with an active comparator drug class (sodium-glucose co-transporter 2 [SGLT2] inhibitors). RESULTS: Among 19,0321 new users of DPP4 inhibitors (median (interquartile range [IQR]) follow-up time, 1.3 [0.6-2.6] years) and 139,315 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4-1.7] years), 919 intestinal obstruction events occurred. Use of DPP4 inhibitors, as compared with SGLT2 inhibitors, was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 2.0 vs 1.8 per 1000 person-years; hazard ratio, 1.13; 95% confidence interval, 0.96-1.34). Among 121,254 new users of GLP-1 receptor agonists (median [standard deviation] follow-up time, 0.9 [0.4-1.9] years) and 185,027 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4-1.8] years), 557 intestinal obstruction events occurred. Use of GLP-1 receptor agonists was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 1.3 vs 1.6 per 1000 person-years; hazard ratio, 0.83; 95% confidence interval, 0.69-1.01). CONCLUSIONS: In this analysis of nationwide data from 3 countries, previous safety signals indicating an increased risk of intestinal obstruction with use of DPP4 inhibitors and GLP-1 receptor agonists were not confirmed.

Cardiac Characteristics of the First Two Waves of COVID-19 in Denmark and the Prognostic Value of Echocardiography: The ECHOVID-19 Study.

INTRODUCTION: COVID-19 has spread globally in waves, and Danish treatment guidelines have been updated following the first wave. We sought to investigate whether the prognostic values of echocardiographic parameters changed with updates in treatment guidelines and the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, 20E (EU1) and alpha (B.1.1.7), and further to compare cardiac parameters between patients from the first and second wave. METHODS: A total of 305 patients hospitalized with COVID-19 were prospectively included, 215 and 90 during the first and second wave, respectively. Treatment in the study was defined as treatment with remdesivir, dexamethasone, or both. Patients were assumed to be infected with the dominant SARS-CoV-2 variant at the time of their hospitalization. RESULTS: Mean age for the first versus second wave was 68.7 ± 13.6 versus 69.7 ± 15.8 years, and 55% versus 62% were males. Left ventricular (LV) systolic and diastolic function was worse in patients hospitalized during the second wave (LV ejection fraction [LVEF] for first vs. second wave = 58.5 ± 8.1% vs. 52.4 ± 10.6%, p < 0.001; and global longitudinal strain [GLS] = 16.4 ± 4.3% vs. 14.2 ± 4.3%, p < 0.001). In univariable Cox regressions, reduced LVEF (hazard ratio [HR] = 1.07 per 1% decrease, p = 0.002), GLS (HR = 1.21 per 1% decrease, p < 0.001), and tricuspid annular plane systolic excursion (HR = 1.18 per 1 mm decrease, p < 0.001) were associated with COVID-related mortality, but only GLS remained significant in fully adjusted analysis (HR = 1.14, p = 0.02). CONCLUSION: Reduced GLS was associated with COVID-related mortality independently of wave, treatment, and the SARS-CoV-2 variant. LV function was significantly impaired in patients hospitalized during the second wave.

Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes.

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.

Association of AZD1222 and BNT162b2 COVID-19 Vaccination With Thromboembolic and Thrombocytopenic Events in Frontline Personnel : A Retrospective Cohort Study.

BACKGROUND: In March 2021, several European countries suspended the use of the AZD1222 (Oxford-AstraZeneca) COVID-19 vaccine because of thromboembolic safety concerns. Reports from Norway and Germany subsequently described patients with venous thrombosis and thrombocytopenia within 5 to 16 days of vaccination. OBJECTIVE: To evaluate the risk for outcomes related to thrombosis and thrombocytopenia after AZD1222 or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccination. DESIGN: Nationwide exploratory retrospective cohort study. SETTING: Danish linkable registers on vaccinations, hospitalizations, occupation, and other covariates. PARTICIPANTS: 355 209 Danish frontline personnel designated for priority COVID-19 vaccination followed from 27 December 2020 (the day of the first COVID-19 vaccination in Denmark) to 13 April 2021. MEASUREMENTS: Study outcomes were cerebral venous sinus thrombosis, splanchnic vein thrombosis, pulmonary embolism, deep venous thrombosis, arterial thrombosis, thrombocytopenia, and death. Cumulative incidences of study outcomes within 28 days of vaccination and unvaccinated risk time were compared using adjusted survival curves resulting in risk differences (RDs) at day 28 after vaccination. Adjustment for birth cohort, sex, calendar period, occupation, comorbid conditions, and prescription drug use was included. RESULTS: Vaccination with AZD1222 versus no vaccination was associated with a significant RD at day 28 for deep venous thrombosis (RD, 8.35 [95% CI, 0.21 to 16.49] per 100 000 vaccinations). The RDs for cerebral venous sinus thrombosis (RD, 1.68 [CI, -0.64 to 4.00] per 100 000 vaccinations) and thrombocytopenia (RD, 2.39 [CI, -1.09 to 5.87] per 100 000 vaccinations) were not significant. No adverse associations were seen for BNT162b2 vaccination. LIMITATION: No medical record review; surveillance bias. CONCLUSION: In this exploratory retrospective cohort study among frontline personnel in Denmark, receipt of the AZD1222 vaccine was associated with a small excess risk for deep venous thrombosis. Although the corresponding risks for the more rare and severe thrombotic outcomes (such as cerebral venous sinus thrombosis) were not statistically significantly increased, statistical precision was low, and clinically relevant risks could not be excluded with certainty. There was no statistically significant association of BNT162b2 vaccination with thrombotic or thrombocytopenic events. PRIMARY FUNDING SOURCE: Lundbeck Foundation.

The comparative cardiovascular and renal effectiveness of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: A Scandinavian cohort study.

AIM: To assess the comparative cardiovascular and renal effectiveness of sodium-glucose co-transporter-2 (SGLT2) inhibitors versus glucagon-like peptide-1 (GLP-1) receptor agonists in routine clinical practice. MATERIALS AND METHODS: A cohort study of nationwide registers from Sweden, Denmark, and Norway, including 87 525 new users of SGLT2 inhibitors and 63 921 new users of GLP-1 receptor agonists, was conducted using data from 2013-2018. Co-primary outcomes, analysed using an intention-to-treat exposure definition, were major adverse cardiovascular events (MACE; myocardial infarction, stroke, and cardiovascular death), heart failure (hospitalization or death because of heart failure), and serious renal events (renal replacement therapy, hospitalization for renal events, and death from renal causes). RESULTS: Use of SGLT2 inhibitors versus GLP-1 receptor agonists was associated with a higher risk of MACE (adjusted incidence rate: 15.2 vs. 14.4 events per 1000 person-years; HR 1.07 [95% CI 1.01-1.15]), a similar risk of heart failure (6.0 vs. 6.0 events per 1000 person-years; HR 1.02 [0.92-1.12]), and a lower risk of serious renal events (2.9 vs. 4.0 events per 1000 person-years; HR 0.76 [0.66-0.87]). In as-treated analyses, the HR (95% CI) was 1.11 (1.00-1.24) for MACE, 0.88 (0.74-1.04) for heart failure, and 0.60 (0.47-0.77) for serious renal events. In secondary outcome analyses, use of SGLT2 inhibitors versus GLP-1 receptor agonists was not associated with statistically significant differences for the risk of myocardial infarction (HR 1.09 [95% CI 1.00-1.19]), cardiovascular death (HR 0.97 [95% CI 0.84-1.12]), death from renal causes (HR 0.75 [95% CI 0.41-1.35]), or any cause death (HR 1.01 [95% CI 0.94-1.09]), while the risk of stroke was higher (HR 1.14 [95% CI 1.03-1.26]), and the risk of renal replacement therapy (HR 0.74 [95% CI 0.56-0.97]) and hospitalization for renal events (HR 0.75 [95% CI 0.65-0.88]) were lower among users of SGLT2 inhibitors. CONCLUSIONS: Use of SGLT2 inhibitors versus GLP-1 receptor agonists was associated with a similar risk of heart failure and a lower risk of serious renal events, while use of GLP-1 receptor agonists versus SGLT2 inhibitors was associated with a slightly lower risk of MACE. In as-treated analyses, the associations with MACE and serious renal events increased in magnitude, and the HR for heart failure tended towards a protective association for SGLT2 inhibitors.

A Nationwide Observational Study of Chlamydia trachomatis Infections in Denmark during the COVID-19 Pandemic.

The aim of this study was to determine whether COVID-19 restrictions had an impact on Chlamydia trachomatis infections compared with 2018 and 2019. A retrospective nationwide observational study was performed using monthly incidences of laboratory-confirmed chlamydia cases and number of tests, obtained from Danish national surveillance data. Testing rates and positivity rates were compared using Poisson and logistic regression. The first Danish COVID-19 lockdown (12 March to 14 April 2020) resulted in a reduction in the number of chlamydia tests performed (rate ratio 0.72, 95% confidence interval  0.71-0.73) and a consequent reduction in the number of laboratory-identified cases (66.5 vs 88.3 per 100,000 population during the same period in 2018 to 2019). This period was followed by a return of testing and test positivity close to the level seen in 2018 to 2019. The second Danish COVID-19 lockdown (17 December to 31 March 2021) resulted in crude incidence rates of laboratory-confirmed chlamydia infection that were similar to the crude incidence rates seen during same period in 2018 to 2019. In conclusion, the Danish COVID-19 restrictions have had negligible effects on laboratory-confirmed C. trachomatis transmission.

Preterm birth, stillbirth and early neonatal mortality during the Danish COVID-19 lockdown.

Using provisional or opportunistic data, three nationwide studies (The Netherlands, the USA and Denmark) have identified a reduction in preterm or extremely preterm births during periods of COVID-19 restrictions. However, none of the studies accounted for perinatal deaths. To determine whether the reduction in extremely preterm births, observed in Denmark during the COVID-19 lockdown, could be the result of an increase in perinatal deaths and to assess the impact of extended COVID-19 restrictions, we performed a nationwide Danish register-based prevalence proportion study. We examined all singleton pregnancies delivered in Denmark during the COVID-19 strict lockdown calendar periods (March 12-April 14, 2015-2020, N = 31,164 births) and the extended calendar periods of COVID-19 restrictions (February 27-September 30, 2015-2020, N = 214,862 births). The extremely preterm birth rate was reduced (OR 0.27, 95% CI 0.07 to 0.86) during the strict lockdown period in 2020, while perinatal mortality was not significantly different. During the extended period of restrictions in 2020, the extremely preterm birth rate was marginally reduced, and a significant reduction in the stillbirth rate (OR 0.69, 0.50 to 0.95) was observed. No changes in early neonatal mortality rates were found.Conclusion: Stillbirth and extremely preterm birth rates were reduced in Denmark during the period of COVID-19 restrictions and lockdown, respectively, suggesting that aspects of these containment and control measures confer an element of protection. The present observational study does not allow for causal inference; however, the results support the design of studies to ascertain whether behavioural or social changes for pregnant women may improve pregnancy outcomes. What is Known: • The aetiologies of preterm birth and stillbirth are multifaceted and linked to a wide range of socio-demographic, medical, obstetric, foetal, psychosocial and environmental factors. • The COVID-19 lockdown saw a reduction in extremely preterm births in Denmark and other high-income countries. An urgent question is whether this reduction can be explained by increased perinatal mortality. What is New: • The reduction in extremely preterm births during the Danish COVID-19 lockdown was not a consequence of increased perinatal mortality, which remained unchanged during this period. • The stillbirth rate was reduced throughout the extended period of COVID-19 restrictions.

Risk factors for granulomas in children following immunization with aluminium-adsorbed vaccines: A Danish population-based cohort study.

BACKGROUND: Aluminium-adsorbed vaccines may in some children cause severely itching nodules at the injection site, known as vaccination granulomas. OBJECTIVE: To investigate vaccine-, child- and maternal-level risk factors for the development of vaccination granulomas following immunization with aluminium-adsorbed vaccines. METHODS: A Danish population-based cohort study with 553 932 children born in Denmark from 1 January 2009 to 31 December 2018, vaccinated with an aluminium-adsorbed vaccine during the first year of life, followed until 31 December 2020. Poisson regression was used to estimate granuloma rate ratios according to the type of adjuvant, accumulated dose of aluminium, timing of vaccination appointments, sex, gestational age, having siblings with granulomas, maternal age and maternal ethnicity. RESULTS: We identified 1901 vaccination granuloma cases (absolute risk, 0.34%). Among vaccine level factors, revaccination (third vs. first vaccination appointment, adjusted rate ratio [RR] 1.26, 95% confidence interval [CI] 1.03-1.55), the specific adjuvant used (aluminium phosphate vs. hydroxide, RR 0.58, 95% CI 0.48-0.70) and dosage (≥1.0 mg vs. <1.0 mg, RR 1.34, 95% CI 1.19-1.52) were associated with risk of granulomas; the timing of vaccination appointments was not. Among child-level factors, female sex (vs. males, RR 1.12, 95% CI, 1.02-1.22), prematurity (vs. term birth, RR 0.71, 95% CI, 0.54-0.93) and having sibling(s) with granulomas (vs. no siblings with granulomas, RR 46.15, 95% CI, 33.67-63.26) were associated with risk of granulomas. Among maternal-level factors, non-Danish ethnicity (vs. Danish, RR 0.51, 95% CI, 0.42-0.63) and young maternal age (<20 years vs. 20-39 years, RR 0.46, 95% CI 0.25-0.83) were associated with risk of granulomas. CONCLUSIONS: Several risk factors for vaccination granulomas at the vaccine, child and maternal levels, were identified. Reducing the dose of aluminium or replacing aluminium hydroxide with aluminium phosphate could reduce the risk of granulomas. However, this must be balanced against the potential for reduced immunogenicity.

Proton-Pump Inhibitor Use and the Risk of Community-Associated Clostridium difficile Infection.

BACKGROUND: Proton-pump inhibitors (PPIs) have been reported to increase the risk of community-associated Clostridium difficile infection (CDI), but the association remains disputed. METHODS: A nationwide cohort study among adults in Denmark, 2010-2013, linking register data on C. difficile testing, filled prescriptions, and patient characteristics. All incident episodes of community-associated CDI (ie, positive culture, molecular assay, or toxin test in individuals without previous hospitalization in the prior 12 weeks and without a positive test for C. difficile in the prior 8 weeks) were identified in the Danish National Microbiological Database. Self-controlled case-series analyses were used to estimate incidence rate ratios (IRRs) for community-associated CDI, comparing periods with and without exposure to PPIs. By design, models took fixed confounders such as chronic disease, genetics, and socioeconomic status into account; further, time-varying confounders, including hospital stay and antibiotic and corticosteroid use were adjusted for. RESULTS: 3583 episodes of community-associated CDI were identified, of which 964 occurred during current use of PPIs, 324 occurred 0-6 months after treatment cessation, 123 occurred 6-12 months after treatment cessation, and 2172 occurred during time periods without use of PPIs. The adjusted IRR was 2.03 (95% confidence interval, 1.74-2.36), comparing use of PPI with nonuse. The increased risk remained elevated in later time periods: 1.54 (1.31-1.80) for 0-6 months, 1.24 (1.00-1.53) for 6-12 months after current use. CONCLUSIONS: Use of PPIs was associated with moderately increased risk of community-associated CDI. The risk remained elevated up to 1 year after PPI treatment had ended.

Association between inhaled corticosteroid use and COVID-19 outcomes.

BACKGROUND: Recent evidence has established a beneficial effect of systemic corticosteroids for treatment of moderate-to-severe COVID-19. OBJECTIVE: To determine if inhaled corticosteroid use is associated with COVID-19 outcomes. METHODS: In a nationwide cohort of hospitalized SARS-CoV-2 test-positive individuals in Denmark, we estimated the 30-day hazard ratio of intensive care unit (ICU) admission or death among users of inhaled corticosteroids (ICS) compared with users of bronchodilators (ß2 -agonist/muscarinic-antagonists), and non-users of ICS overall, with Cox regression adjusted for age, sex, and other confounders. We repeated these analyses among influenza test-positive patients during 2010-2018. RESULTS: Among 6267 hospitalized SARS-CoV-2 patients, 614 (9.8%) were admitted to ICU and 677 (10.8%) died within 30 days. ICS use was associated with a hazard ratio of 1.09 (95% CI [CI], 0.67 to 1.79) for ICU admission and 0.78 (95% CI, 0.56 to 1.11) for death compared with bronchodilator use. Compared with no ICS use overall, the hazard ratio of ICU admission or death was 1.17 (95% CI, 0.87-1.59) and 1.02 (95% CI, 0.78-1.32), respectively. Among 10 279 hospitalized influenza patients, of which 951 (9.2%) were admitted to ICU and 1275 (12.4%) died, the hazard ratios were 1.43 (95% CI, 0.89-2.30) and 1.11 (95% CI, 0.85-1.46) for ICU admission, and 0.80 (95% CI, 0.63-1.01) and 1.03 (95% CI, 0.87-1.22) for death compared with bronchodilator use and no ICS use overall, respectively. CONCLUSION: Our results do not support an effect of inhaled corticosteroid use on COVID-19 outcomes, however we can only rule out moderate-to-large reduced or increased risks. STUDY REGISTRATION: The study was pre-registered at encepp.eu (EUPAS35897).

Quadrivalent HPV Vaccination and the Risk of Adverse Pregnancy Outcomes.

BACKGROUND: The quadrivalent human papillomavirus (HPV) vaccine is recommended for all girls and women 9 to 26 years of age. Some women will have inadvertent exposure to vaccination during early pregnancy, but few data exist regarding the safety of the quadrivalent HPV vaccine in this context. METHODS: We assessed a cohort that included all the women in Denmark who had a pregnancy ending between October 1, 2006, and November 30, 2013. Using nationwide registers, we linked information on vaccination, adverse pregnancy outcomes, and potential confounders among women in the cohort. Women who had vaccine exposure during the prespecified time windows were matched for propensity score in a 1:4 ratio with women who did not have vaccine exposure during the same time windows. Outcomes included spontaneous abortion, stillbirth, major birth defect, small size for gestational age, low birth weight, and preterm birth. RESULTS: In matched analyses, exposure to the quadrivalent HPV vaccine was not associated with significantly higher risks than no exposure for major birth defect (65 cases among 1665 exposed pregnancies and 220 cases among 6660 unexposed pregnancies; prevalence odds ratio, 1.19; 95% confidence interval [CI], 0.90 to 1.58), spontaneous abortion (20 cases among 463 exposed pregnancies and 131 cases among 1852 unexposed pregnancies; hazard ratio, 0.71; 95% CI, 0.45 to 1.14), preterm birth (116 cases among 1774 exposed pregnancies and 407 cases among 7096 unexposed pregnancies; prevalence odds ratio, 1.15; 95% CI, 0.93 to 1.42), low birth weight (76 cases among 1768 exposed pregnancies and 277 cases among 7072 unexposed pregnancies; prevalence odds ratio, 1.10; 95% CI, 0.85 to 1.43), small size for gestational age (171 cases among 1768 exposed pregnancies and 783 cases among 7072 unexposed pregnancies; prevalence odds ratio, 0.86; 95% CI, 0.72 to 1.02), or stillbirth (2 cases among 501 exposed pregnancies and 4 cases among 2004 unexposed pregnancies; hazard ratio, 2.43; 95% CI, 0.45 to 13.21). CONCLUSIONS: Quadrivalent HPV vaccination during pregnancy was not associated with a significantly higher risk of adverse pregnancy outcomes than no such exposure. (Funded by the Novo Nordisk Foundation and the Danish Medical Research Council.).

Measles, Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study.

Background: The hypothesized link between the measles, mumps, rubella (MMR) vaccine and autism continues to cause concern and challenge vaccine uptake. Objective: To evaluate whether the MMR vaccine increases the risk for autism in children, subgroups of children, or time periods after vaccination. Design: Nationwide cohort study. Setting: Denmark. Participants: 657 461 children born in Denmark from 1999 through 31 December 2010, with follow-up from 1 year of age and through 31 August 2013. Measurements: Danish population registries were used to link information on MMR vaccination, autism diagnoses, other childhood vaccines, sibling history of autism, and autism risk factors to children in the cohort. Survival analysis of the time to autism diagnosis with Cox proportional hazards regression was used to estimate hazard ratios of autism according to MMR vaccination status, with adjustment for age, birth year, sex, other childhood vaccines, sibling history of autism, and autism risk factors (based on a disease risk score). Results: During 5 025 754 person-years of follow-up, 6517 children were diagnosed with autism (incidence rate, 129.7 per 100 000 person-years). Comparing MMR-vaccinated with MMR-unvaccinated children yielded a fully adjusted autism hazard ratio of 0.93 (95% CI, 0.85 to 1.02). Similarly, no increased risk for autism after MMR vaccination was consistently observed in subgroups of children defined according to sibling history of autism, autism risk factors (based on a disease risk score) or other childhood vaccinations, or during specified time periods after vaccination. Limitation: No individual medical charts were reviewed. Conclusion: The study strongly supports that MMR vaccination does not increase the risk for autism, does not trigger autism in susceptible children, and is not associated with clustering of autism cases after vaccination. It adds to previous studies through significant additional statistical power and by addressing hypotheses of susceptible subgroups and clustering of cases. Primary Funding Source: Novo Nordisk Foundation and Danish Ministry of Health.

Genetic regulation of gene expression in the epileptic human hippocampus.

Epilepsy is a serious and common neurological disorder. Expression quantitative loci (eQTL) analysis is a vital aid for the identification and interpretation of disease-risk loci. Many eQTLs operate in a tissue- and condition-specific manner. We have performed the first genome-wide cis-eQTL analysis of human hippocampal tissue to include not only normal (n = 22) but also epileptic (n = 22) samples. We demonstrate that disease-associated variants from an epilepsy GWAS meta-analysis and a febrile seizures (FS) GWAS are significantly more enriched with epilepsy-eQTLs than with normal hippocampal eQTLs from two larger independent published studies. In contrast, GWAS meta-analyses of two other brain diseases associated with hippocampal pathology (Alzheimer's disease and schizophrenia) are more enriched with normal hippocampal eQTLs than with epilepsy-eQTLs. These observations suggest that an eQTL analysis that includes disease-affected brain tissue is advantageous for detecting additional risk SNPs for the afflicting and closely related disorders, but not for distinct diseases affecting the same brain regions. We also show that epilepsy eQTLs are enriched within epilepsy-causing genes: an epilepsy cis-gene is significantly more likely to be a causal gene for a Mendelian epilepsy syndrome than to be a causal gene for another Mendelian disorder. Epilepsy cis-genes, compared to normal hippocampal cis-genes, are more enriched within epilepsy-causing genes. Hence, we utilize the epilepsy eQTL data for the functional interpretation of epilepsy disease-risk variants and, thereby, highlight novel potential causal genes for sporadic epilepsy. In conclusion, an epilepsy-eQTL analysis is superior to normal hippocampal tissue eQTL analyses for identifying the variants and genes underlying epilepsy.